RDEB SCC gene sequencing

Completed Projects, EB Cancer Therapy, Whole Body Treatment
About This Project

Deep sequencing Recessive Dystrophic Epidermolysis Bullosa squamous cell carcinoma

Lay summary

Patients with Recessive Dystrophic Epidermolysis Bullosa (RDEB) frequently develop aggressive, life-threatening squamous cell carcinoma (SCC) – a skin cancer – the reasons for which are incompletely understood.

The results of this project showed that RDEB cancers are more similar, in many ways, to cancers in the general public which arise in the mouth, rather than SCC caused by ultraviolet light. This observation may help to explain why RDEB cancers are very aggressive, because mortality rates in the general population are higher for mouth cancers compared with similar skin cancers.

Mutations associated with microbial infection are enhanced in RDEB cancer which may lead to new ideas for cancer prevention.

Finally, the data show several pathways which can be targeted with new therapies are activated in RDEB cancer, and this study now provides a basis for studying these targets for treatment development.

Scientific Summary

This project used massively parallel sequencing to determine the spectrum of mutation in all protein coding genes in cutaneous squamous cell carcinoma (cSCC) excised from patients with RDEB and compared these data with spontaneous, UV-induced cSCCs, to test the hypotheses that RDEB cSCCs share common mutations that enable this cancer to develop so quickly and in the absence of lifelong sun exposure and DNA damage. The aim was to find tractable therapy options by matching known chemotherapies to genetic mutations and to delineate new targets for future development, both clinically and experimentally.

The results of this project showed that DEB SCC harbour similar mutation burden compared with other SCC of the skin and oral cavity:

  • RDEB SCC mutation burden is similar to oral cavity SCC
  • UV, APOBEC and CLOCK-like signatures contribute to RDEB SCC mutation
  • HRAS mutation is higher in RDEB SCC compared with sporadic skin and oral cavity SCC suggesting that MAPK inhibitors or the RAS-mimetic rigosertib may have clinical application for treating RDEB SCC
  • Copy number variation is reduced in RDEB SCC compared with sporadic SCC
  • MADCAM1 mutation is identified in adjacent, normal appearing epidermal tissue in RDEB suggesting that this may be a novel, early event in RDEB SCC
  • RNA sequencing identifies RDEB SCC are more similar to “basal”-like oral cavity SCC at the level of gene expression
  • RDEB SCC show elevated expression of the APOBEC3 family of enzymes, likely resulting in increased APOBEC mutation signature in the majority of tumours analysed.

Related Publications

Cho, R.J., et al. APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa. Science Translational Medicine 2018;10(455)